The present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular, the compound disclosed and referred to as "Compound J" in EPO 541,168, which published on May 12, 1993, or pharmaceutically acceptable salts thereof. ##STR1## These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
More specifically, the instant process involves the racemization of optically pure or enriched piperazine-2-tert-butylcarboxamide and derivatives with strong base, anhydrous metal salts or carboxylic acids under mild conditions. The piperazine-tert-butylcarboxamide derivatives are key intermediates useful in the preparation of HIV protease inhibitor compounds, including Compound J.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including Compound J which is shown in Example 20 below, that can be made from the novel intermediates and process of this invention are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993.
Previously, the synthesis of Compound J and related compounds was accomplished via a 12-step procedure which employed a hydroxy protected dihydro-5(S)-hydroxymethyl-3(2H) furanone which was alkylated, and involved replacement of an alcohol leaving group on the alkylated furanone with a piperidine moiety. The coupled product was then hydrolyzed to open the furanone ring into a hydroxy acid moiety, and the acid was ultimately coupled to 2(R)-hydroxy-1(S)-aminoindane. This procedure is described in EPO 541,168. The extreme length of this route (12 steps), renders this process time consuming and labor intensive, and it requires the use of many expensive reagents and an expensive starting material. A route requiring fewer reaction steps and reagents would provide desirable economical and time-saving benefits.
A modified route to Compound J and related compounds was also shown in EPO 541,168 based on the diastereoselective alkylation of the enolate derived from N-(2(R)-hydroxy-1(S)-indan-N,O-isopropyl-idene-yl)-3-phenyl-propaneamide, in which the C.sub.3 -C.sub.5 three-carbon unit was introduced as an allyl group and later oxidized. Some problems with this route are: (a) four steps are necessary to effect the introduction of the three carbon glycidyl fragment, (b) highly toxic OsO.sub.4 is used in the process and (c) low diastereoselectivity is obtained in the dihydroxylation step. Thus, a desirable process would directly introduce the three carbon unit in the correct chiral oxidized form.
Furthermore, the synthesis of the chiral piperazine intermediate was effected from 2-pyrazinecarboxylic acid in a 6 step procedure and required the use of expensive reagents such as BOC-ON and EDC. A shorter route to the piperazine intermediate which also does not use expensive reagents would thus be desired. Moreover, during the synthesis of the chiral piperazine intermediate, both the desired (S)-piperazine carboxylate enantiomer (i.e., the precursor to the 2(S)-carboxamide piperazine intermediates) and the undesired (R)-enantiomer are formed requiring separation of the desired (S)-enantiomer which is then carded on to ultimately form Compound J. In the absence of practical methodology for converting the (R)-antipode to the (S)-antipode, it was discarded as waste, thus limiting the possible efficiency of this step to 50%. Thus, a method to improve the recovery of the (S)-piperazine intermediate would be highly desirable.
More recently, a shorter route for preparing the compounds disclosed in EPO 541,168, and in particular Compound J, has been found. In this new route, 1-((R)-2',3'-Epoxypropyl-(S)-2-tert-butylcarbonyl-piperazine is prepared and reacted with N-(2(R)-hydroxy-1(S)-indan-N,O-isopropylidene-yl)-3-phenylpropaneamide to give the coupled product 8. ##STR2## After removal of the BOC protecting group from the piperazine nitrogen, the unprotected piperazine compound is then reacted with 3-picolyl chloride to form Compound J.
As with the earlier described process for preparing the HIV protease inhibitor compounds disclosed in EPO 541,168, preparation of the key chiral piperazine intermediate in this new process still results in a mixture of enantiomers requiting resolution of the (S)-enantiomer which is then carried on to form the final product. In the absence of practical methodology for converting the undesired (R)-antipode to the (S)-antipode, it was discarded as waste, thereby limiting the possible efficiency of this step to 50% and resulting in considerable waste and expense. Thus, a method to increase the yield of the (S)-piperazine intermediate would be highly desirable, resulting in both a reduction of the capital costs associated with the synthesis of Compound J and a reduction of the environmental problems caused by production of large quantities of unusable organic salt.
The racemization of amides and peptides under basic conditions is known, and can occur via deprotonation of the asymmetric carbon atom to form an enolate, followed by reprotonation (eq. 1). ##STR3## With amides bearing a heteroatom in the 2-position, racemization is also known to occur via elimination of the heteroatom followed by Michael-type readdition of the heteroatom to the unsaturated species (eq. 2). As this unsaturated species is a monomer prone to polymerization, low yields of racemized product result. ##STR4## See, Advances in Protein Chemistry, Anson, M. L., Edsall, J. T., ed. Volume IV, Academic Press, New York, 1948, 344-356.
Conditions typically employed to racemize peptides, however, do not work in the case of the piperazine-2-tert-butylcarboxamide derivatives of the instant invention because the hydrogen, which is on the carbon atom of the piperazine ring, is very weakly acidic and is therefore difficult to remove. Thus, it was unexpected and unpredictable that racemization of the piperazine-2-tert-butylcarboxamides could be efficiently and rapidly carded out under mild conditions.
The instant invention provides a method for increasing the yield of the desired (S)-piperazine intermediate X, which is needed in the synthesis of Compound J, by racemizing optically pure or enriched piperazine-2-tert-butyl-carboxamide and derivatives with strong base under mild conditions. Since the optically active piperazine-2-tert-butylcarboxamides are available via resolution of the corresponding racemates, subsequent racemization of the undesired antipode provides a way to recycle it into the desired antipode, thereby increasing the yield, eliminating waste and resulting in capital savings. Thus, the instant invention provides a more advantageous method for preparing HIV protease inhibitors containing the 2(S)-carboxamide piperazine moiety than previously known by allowing a higher yielding synthesis of the compounds useful in the treatment of HIV, and in particular Compound J, by increasing recovery of the 2(S)-carboxamide piperazine intermediate.